Over-representation analysis of angiogenic factors in immunosuppressive mechanisms in neoplasms and neurological conditions during COVID-19.

Background: Recent studies emphasized the necessity to identify key (human) biological processes and pathways targeted by the Coronaviridae family of viruses, especially Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronavirus Disease (COVID-19) caused up to 33-55 % death rates in COVID-19 patients with malignant neoplasms and Alzheimer's disease. Given this scenario, we identified biological processes and pathways involved in various diseases which are most likely affected by COVID-19.

Methods: The COVID-19 DisGeNET data set (v4.0) contains the associations between various diseases and human genes known to interact with viruses from Coronaviridae family and were obtained from the IntAct Coronavirus data set annotated with DisGeNET data. We constructed the disease-gene network to identify genes that are involved in various comorbid diseased states. Communities from the disease-gene network were identified using Louvain method and functional enrichment through over-representation analysis methodology was used to discover significant biological processes and pathways shared between COVID-19 and other diseases.

Result: The COVID-19 DisGeNET data set (v4.0) comprised of 828 human genes and 10,473 diseases (including various phenotypes) that together constituted nodes in the disease-gene network. Each of the 70,210 edges connects a human gene with an associated disease. The top 10 genes linked to most number of diseases were VEGFA, BCL2, CTNNB1, ALB, COX2, AGT, HLA-A, HMOX1, FGF2 and COMT. The most vulnerable group of patients thus discovered had comorbid conditions such as carcinomas, malignant neoplasms and Alzheimer's disease. Finally, we identified 15 potentially useful biological processes and pathways for improved therapies. Vascular endothelial growth factor (VEGF) is the key mediator of angiogenesis in cancer. It is widely distributed in the brain and plays a crucial role in brain inflammation regulating the level of angiopoietins. With a degree of 1899, VEGFA was associated with maximum number of diseases in the disease-gene network. Previous studies have indicated that increased levels of VEGFA in the blood results in dyspnea, Pulmonary Edema (PE), Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). In case of COVID-19 patients with neoplasms and other neurological symptoms, our results indicate VEGFA as a therapeutic target for inflammation suppression. As VEGFs are known to disproportionately affect cancer patients, improving endothelial permeability and vasodilation with anti-VEGF therapy could lead to suppression of inflammation and also improve oxygenation. As an outcome of our study, we make case for clinical investigations towards anti-VEGF therapies for such comorbid conditions affected by COVID-19 for better therapeutic outcomes.